Naphtho(2,1-d)isoxazole derivatives

ABSTRACT

1. A COMPOUND OF THE FORMULA   3-(R-CH2-)-NAPHTHO(2,1-D)ISOXAZOLE   WHEREIN RING A HAS 0-2 SUBSTITUENTS SELECTED FRM THE GROUP CONSISTING OF ALKOXY OF UP TO 4 CARBON ATOMS, ALKYL OF UP TO 4 CARBON ATOMS, AND HALOGEN, RING B MAY HAVE A CARBON-TO-CARBON DOUBLE BOND BETWEEN THE POSITION OF C-4 AND C-5, AND R REPRESENTS A HYDROXYL GROUP, A HALOGEN ATOM OR A CYANO GROUP.

Claims ABSTRACT OF THE DISCLOSURE 3-substituted naphth[2,1-d]isoxazoles and their derivatives and a process for producing the same, the isoxazoles being represented by the formula 1n l l wherein the ring A may be substituted or unsubstituted, the ring B may have a carbon-to-carbon double bond between the positions of C-4 and C-5, and R represents a hydroxyl group, a halogen atom, or a cyano group.

This application is a divisional application of our copending application Ser. No. 864,163 filed on Oct. 6, 1969, now abandoned. This invention relates to a novel 3-substituted naphth[2,1-d]isoxazolyl derivative and to a process for preparing the same.

According to this invention, a 3-substituted naphth[2,1 d]isoxazolyl derivative expressed by the general formula I i CHg-R B wherein the ring A may be substituted or unsubstituted, the ring B may have a carbon-to-carbon double bond between the positions of C-4 and C5, and R represents a hydroxyl group, a halogen atom or a cyano group is provided.

In the above general formula (I), the ring A may be mono-, dior tri-substituted with optional substituents; for instance, alkoxy groups such as methoxy, ethoxy, nor iso-propoxy and n-, iso-, secor tert-butyl, preferably alkoxy groups of 4 or less carbon atoms; alkyl groups such as methyl, ethyl and nor iso-propyl, preferably alkyl groups of 4 or less carbon atoms; and halogen atoms such as bromine, chlorine, and iodine. The ring B may either be saturated between the positions of C-4 and C-5 or have a carbon-to-carbon double bond between the positions of C-4 and C-5.

Novel compounds expressed by above general formula (I) are divided into the following three groups.

Compounds of the first group are 3-hydroxymethylnaphth[2,1-d]isoxazoles and their derivatives expressed by the following general formula:

AHB

United States Patent 0 ice wherein the rings A and B are as defined in general formula (I).

Examples of the compounds expressed by above general formula (II) are as follows:

3-hydroxymethyl-8-methoxy-4,S-dihydro-naphth[2,l-d]

isoxazole, 3-hydroxymethyl-7-methoxy-4,S-dihydro-naphth[2, l-d] isoxazole, 3 -hydroxymethy1- 6-ethoxy-4,5-dihydro-naphth [2, l-d] isoxazole, 3-hydroxymethyl-7-methoxy-6-chloro-4,5-dihydro-naphth [2,1-d1isoxazole, 3-hydroxymethy1-8-methoxy-naphth[2,1-d]isoxazole, 3-hydroxymethyl-7-methoxy-naphth[2,1-d]isoxazole, and 3-hydr0xymethy1-7-methoxy-fi-chloro-naphth 2, l-d] isoxazole.

Compounds of the second group included in the novel compounds of above general formula (I) are 3-halomethyl-naphth[2,1-d]isoxazoles and their derivatives expressed by the following general formula:

l A I B (III) wherein X stands for a halogen atom such as chlorine, bromine or iodine, particularly a chlorine atom, and the rings A and B are as defined in above general formula Examples of the compounds expressed by above general formula (III) are as follows:

3-chloromethy1-8-methoxy-4,5-dihydro-naphth[2,1-d]

isoxazole, 3-chloromethy1-7-methoxy-4,5-dihydro-naphth[2,1-d]

isoxazole, 3-chloromethyl-6-ethoxy-4,S-dihydro-naphth [2,1-d]

isoxazole, 3-bromomethyl-8-methoxy-4,S-dihydro-naphth[2,1-d]

isoxazole, 3-bromomethyl-7-methoxy-4,S-dihydro-naphth [2,1-d]

isoxazole, 3-brornomethyl-6-ethoxy-4,S-dihydro-naphth[2,1d]

isoxazle, 3-bromomethyl-8-ethyl-4,5-dihydro-naphth[2,1-d]

isoxazole, 3-bromomethy1-7-ethyl-4,5-dihydro-naphth[2,1-d]

isoxazole, 3-chloromethyl-4,-5-dihydro-naphth[2,1-d]isoxazole, 3-bromomethy1-4,S-dihydro-naphth[2,1-d]isoxazo1e, 3 -chloromethy1-8-methoxy-naphth[2,1-d] isoxazole, 3-chloromethy1-8-methoxy-7-chloro-naphth [2, l-d] isoxazole, 3-chlorornethyl-7-methoxy-naphth[2,1-d1isoxazole, 3-chloromethy1-7-methoxy-6-chloro-naphth[2,1-d]

isoxazole, 3-bromomethyl-naphth[2, 1-d] isoxazole, 3-bromomethy1-S-methoxy-naphth [2, l-d] isoxazole, and 3-bromomethyl-7-methoxy-naphth[2, 1-d]isoxazole.

Compounds of the third group included in the compounds expressed by above general formula (I) are 3- cyanomethyl-naphth[2,1-d]isoxazoles and their derivatives expressed by the following formula:

I CW

wherein the rings A and B are as defined above in above general formula (I).

As specific examples of the compound (IV), the following compounds may be cited:

Novel compounds of this invention expressed by above general formulae (II), (III) and (IV) may be synthesized by methods which will be illustrated below.

Compounds expressed by above general formula (H) can be synthesized by reducing a compound expressed by the following general formula:

oooa

wherein -R represents a hydrogen atom, an alkyl group,

an alkali metal, an alkaline earth metal or an ammonium group, and rings A and B are as defined in general formula (I),

by a method known per see.

More specifically, the reduction of compounds of the formula (V) can be performed by employing a metal hydride such as an alkali metal aluminum hydride, e.g., LiAlH and an alkali metal boron hydride, e.g., NaBH4; a hydrogenated metal complex such as sodium dihydrobis (Z-methoxyethoxy) aluminate or a combination of an alcohol with an alkali or alkaline earth metal. Further, for instance, a combination of a mineral acid such as hydrochloric acid with a metal such as zinc may be used. Of course, the reducing agent to be used in this invention should not be one which reduces the isoxazole ring.

The reduction of the compound of the formula (V) can be performed by dissolving or suspending the compound into an organic solvent inert to the reaction, for instance, an ether such as tetrahydrofuran and ethyl ether; an aromatic hydrocarbon such as benzene, toluene and xylene; an alcohol such as methanol, ethanol and 'butanol; or a carboxylic acid such as acetic acid, and adding the above mentioned reducing agent to the solution or suspension.

The reaction temperature is not particularly critical, but the reaction is generally conducted at a temperature ranging from room temperature to the boiling point of the solvent used, preferably from 25 to 150 C. The reaction is performed sufficiently under atmospheric pressure, but it is possible to carry out the reaction under elevated pressure.

The intended hydroxy methyl product of the formula (H) can be isolated in a pure form by distilling" off th organic solvent from the reaction mixture, throwing the residue into a non-solvent such as water, and recovering the insoluble matter by filtration or extraction, if necessary, followed by recrystallization or chromatography.

Compounds of above general formula (V) in which ring B is saturated between the positions of C-4 and C-5, which are to be used as starting compounds in the above reaction, may be synthesized by reacting a known l-oxo- 1,2,3,4-tetrahydro 2 naphthylglyoxylic acid alkyl ester expressed by the general formula wherein R represents an alkyl group, and ring A is as defined in general formula (I),

with hydroxyl amine or its salt according to a method known per se. The so formed compounds expressed by the following general formula:

I ll

wherein R and ring A are as defined above,

may be converted by the hydrolysis employing an acid or alkali to the corresponding free carboxylic acids in which R in above general formula (V) stands for a hydrogen atom.

The preparation of 4,5-dihydro-naphth[2,1-d]isoxazolyl-3-carboxylic acid esters of the formula (V') from 1- oxo-1,2,3,4-tetrahydro 2 naphthylglyoxylic acid alkylesters of the formula (VI) and hydroxylamine, and the preparation of the free carboxylic acids from the esters of the formula (V') may be conducted in accordance with the method proposed in publication No. 25,656/67 of Japanese patent application or similar methods.

Compounds of general formula (V) in which the ring B has a carbon-to-carbon double bond between the positions of C-4 and C-5 may be obtained by subjecting the so formed esters of general formula (V') or the corresponding free carboxylic acids to cyclo-dehydrogenation treatment.

The cyclo-dehydrogenation treatment may be accomplished, for instance, in an organic solvent which is inert to the reaction under such mild conditions as will not cause any change in the isoxazole ring by employing an ordinary dehydrogenating agent. Dehydrogenating agents particularly suitable for accomplishing the above-mentioned cyclo-dehydrogenation treatment include:

(1) chloranil and DDQ (dichlorodicyanobenzoquinone);

(2) mild oxidants such as anhydrous chromic acid in acetic acid;

(3) molecular halogens such as Cl ,Br and I and (4) phosphorus pentahalides such as PCl and P'Br Reaction conditions vary depending upon the class of the dehydrogenating agent, but the dehydrogenation is generally carried out at temperatures ranging from room temperature to 200 C.

In the case of using a dehydrogenating agent such as chloranil and DDQ, it is preferable to carry out the dehydrogenation with the use of an inert organic solvent such as benzene, toluene and xylene at the boiling point of the solvent. In the case of using anhydrous chromic ,acid in acetic acid as the dehydrogenating agent, it is desired to perform the reaction at a temperature within a range from room temperature to 50 C. When the re acnon mp a re excee s the a ove r g he side reaction occurs at the isoxazolering. When using a molecular halogen as the dehydrogenating agent, it is preferable to dissolve the molecular halogen into a halogenated hydrocarbon medium such as carbon tetrachloride and chloroform, and to conduct the reaction at the boil ing point of the solvent to be used. In this case, the reaction may be conducted with or without the aid of an activating agent such as a catalyst or light. In the case of using a phosphorus pentahalide as the dehydrogenating agent, a phosphorus trihalide, a phosphorus oxyhalide, a halogenated hydrocarbon and other inert organic solvent such as benzene are used as the reaction medium and preferably the reaction may be carried out at the boiling point of the solvent to be used.

In the case of using a molecular halogen or a phosphorus pentahalide, the use of such dehydrogenating agent in an excessive amount sometimes results in the introduction of a halogen substituent into ring A of the naphthoisoxazole, but the introduction of such halogen substituent does not bring about any disadvantage with respect to the object of this embodiment of introducing a carbon-to-carbon double bond between the positions of C4 and C5 of ring B of the 4,S-dihydronaphthisoxazole.

Compounds of general formula (II) in which ring B has a carbon-to-carbon double bond between the positions of C4 and C5 may be formed by subjecting the so obtained compounds of general formula (II) in which the ring B is saturated between the positions of C4 and C5 to the above-mentioned cyclo-dehydrogenation treatment, or by employing as starting reagents compounds of general formula (V) in which ring B has a carbon-tocarbon double bond between the positions of C4 and C5.

Novel compounds of the second group of this invention, namely halomethyl compounds expressed by general formula (III), may be prepared by halogenating the so obtained hydroxymethyl compounds of general formula (II) under known halogenation conditions.

The halogenation of the hydroxymethyl compound of the formula (II) may be carried out under halogenation conditions known per se. Of course, the halogenation reagent to be used should not be one that reacts with the isoxazole ring. The halogenation reagents to be used include a phosphorus trihalide such as PCl PBr and P1 a phosphorus pentahalide such as PCl and PBr or a phosphoryl halide such as POCl and POBr It is preferable to conduct the reaction with the use of such hydrogenation reagent in an amount greater than the equivalent amount based on the hydroxymethyl product of the formula (II), especially 1 to 3 equivalents. When the hydrogenation reagent is used in an amount greater than the equivalent amount, the dehydrogenation between the positions of C4 and C5 of ring B namely, the formation of a double bond between the positions of C4 and C-5 and the halogenation of ring A as well as the halogenation of the hydroxymethyl group sometimes occur coincidentally in the compounds saturated between the positions of C4 and C5 depending upon the polarity of the solvent to be used. Even though such reactions occur, it does not disturb the attainment of the object of this invention.

The reaction temperature is not particularly critical but generally a temperature ranging from 50 to 150 C. is adopted. As the reaction medium, inert organic solvents for instance, halogenated hydrocarbons such as carbon tetrachloride, chloroform, and chlorobenzene; hydrocarbons such as benzene, toluene, xylene and kerosene; or ethers such as ethyl ether, and tetrahydrofuran are preferably used. Also, the reaction is conducted at the boiling point of the solvent to be used.

Compounds of general formula (III) in which ring B has a carbon-to-carbon double bond between the positions of C4 and C5 may be prepared by subjecting the so obtained compounds of general formula (III) in which ring B is saturated between the positions of C4 and 6 0-5 to the above-mentioned cyclo-dehydrogenation treatment or by employing as starting reagents compounds of general formula (II) in which ring R has a carbon-tocarbon double bond between the positions of C4 and C5.

Compounds of the third group of this invention, namely cyanomethyl compounds expressed by general formula (IV), may be formed by reacting the so obtained halomethyl compounds of general formula (III) with an inorganic cyano compound.

Any inorganic cyano compound that is generally known to react with an alkyl halide can be used as the inorganic cyano compound. For instance, inorganic cyano compounds of the formula M (CNL, (VII) wherein M is (a) a metal (such as an alkali metal, e.g., sodium, potassium or lithium, an alkaline earth metal, e.g., calcium, magnesium or barium, and silver, copper, mercury, zinc or lead), (b) ammonium, (c) hydrogen or (d) a cyano group, and n is the valence of M may be preferably used.

The reaction between the halide of the formula (III) and the inorganic cyano compound can be performed under conditions known per se. For instance, this cyanogenation reaction may be conducted in the presence of a polar substance at a temperature ranging from room temperature to the boiling point of the reaction system, preferably from 50 to C. The reaction may be performed sufliciently under atmospheric pressure, but of course, it is possible to carry out the reaction under either reduced or elevated pressures. As the polar substance water; lower alcohols such as methanol and ethanol; carboxylic acids such as formic acid, oxalic acid and acetic acid; ethers such as tetrahydrofuran and ethyl ether; halogenated aliphatic hydrocarbons such as chloroform and dichloroethane; N,N-di-substituted acylamides such as dimethyl formamide, diethyl formamide and dimethyl acetamide; and di-substituted sulfoxides such as dimethyl sulfoxide may be used and diethyl sulfoxide. These polar substances may be used in the state added to an organic solvent which is non-polar by itself.

Compounds of formula (IV) in which ring B has a carbon-to-carbon double bond between the positions of C4 and C-5 may be prepared by subjecting the so obtained compounds of formula (IV) in which ring B is saturated between the positions of C4 and C-5 to the above-mentioned cyclo-dehydrogenation treatment, or by employing as starting reagents compounds of formula (III) in which ring B has a carbon-to-carbon double bond between the positions of C4 and 0-5.

The so obtained compounds of general formula (I), namely compounds expressed by general formulae (II), (III) and (IV), are important intermediates leading to naphth[2,1-d]isoxazolyl alkanoic acids and their derivatives and salts of the following general formula which have excellent analgesic, antipyretic and anti-inflammatory activities and which are superior to non-steroidal anti-inflammatory medicines by their high pharmacological activities and low toxicity:

wherein ring A may be substituted or unsubstituted, ring B may have a carbon-to-carbon double bond between the positions of C4 and C-5, and R stands for a hydroxyl group, a group OM (in which M is sodium, potassium, aluminum, magnesium, calcium or ammonium), an alkoxy group, an optionally substituted amino group, an optionally substituted aminoalkyl amino group, an optionally substituted aminoalkoxy group, a morpholino group, a piperidino group, an N- alkylpiperazino group or a pyrrolidino group.

For instance, compounds of general formula (VIII) in which R stands for a hydroxyl or amino group, namely compounds of the following formula (VIII'),

i ll Oycmoow Al B (VIII) wherein R represents a hydroxyl or amino group, and

the rings A and B are as defined above,

may be synthesized by hydrolyzing a cyanomethyl compound of general formula (IV) or by reacting a halomethyl compound of general formula (III) with an inorganic cyano compound in the presence of water.

The preparation of pharmaceutically useful compounds of general formula (VIII) from novel compounds of general formula (I) and the utilization of the compounds of above general formula (VIII) are detailed in the specification of our copending application Ser. No. 864,163 as follows:

The novel compounds of this invention expressed by the above-mentioned general formula (I) [general formula (I) in Ser. No. 864,163 is the same as general formula (VIII) of the instant application] have excellent analgesic anti-pyretic and anti-inflammatory activities, and have a prominent advantage that they exhibit a much partial hydrolysis (water) ON I I hydrolysis M CHzCONHz CHZCOOH l B Qt (VIIlb) lower toxicity as compared with conventional nonsteroidal anti-inflamation agents. They have another advantage that in the oral administration they do not cause any troubles to digestive organs, particularly any gastroenteric disturbances or disorders.

Accordingly, the novel compounds of this invention may be used in forms of various formulations for remedy of arthritis, rheumatism and other various inflammatory diseases. The novel naphthisoxazolyl alkanoic acids and their derivatives may be administered to patients orally or by hypodermic or intramuscular injection. For the oral administration, the novel compounds of this invention may be blended with a carrier known per se such as lactose, starch, talc, magnesium carbonate, alumina,

tragacanth gum or arabic rubber and applied in the form I of powder, tablets, capsules, granules or the like, or they may be applied in the form of a liquid formulation prepared by dispersing them into a liquid carrier such as water and syrup. For the hypodermic or intramuscular injection, the novel compounds of this invention may be administered in the form dissolved or dispersed in sodium chloride physiological solution or sterilized distilled water.

The suitable doses of the novel compounds of this invention must be diiferentially decided depending on the condition, age, sex, medical history and constitution of a patient and the class of the compound to be administered, but generally, sufiicient curing effects can be attained by an administration of 10 to 100 mg. per dose, 10 to 300 mg. per day.

Generally, the pharmaceutically useful compounds of general formula (VIII) may be synthesized from novel compounds of this invention expressed by general formula (I) through the following reaction routes:

CHzOH A i B lhalogenation A i E (III) lcyanization I -CH2CN B hydrolysis hydrolysis (acid or alkali) (base) l l CHQCOOM B (VIIIa) halogenation \\MOH I I CH'aCOOM R won \HN/ l/ \r R ON O-N More 0 00R Mon, 0 0 N/ (VIIIc) (VIIId) In each of the above formulae, R stands for an alkyl group or a group R! R1 N/ R9 (in which R represents an alkylene group, R and R which may be the same or different, stand for a hydrogen atom or an alkyl group, or they may form together with the nitrogen atom a heterocyclic ring which may further comprise an oxygen, sulfur or nitrogen atom), R and R which may be the same or different, represent a hydrogen atom, an alkyl group or a group R9 M stands for a residue of a base, and X, M, and the rings A and B are as defined above.

In a preferable embodiment of the process described above, the cyano group containing compound of the above-mentioned formula (IV) is formed and then subjected to hydrolysis after or without the isolation of the compound of formula (IV). Further, the cyanogenation of the halide of the formula (III) and the hydrolysis of the cyano group may be performed coincidentally by conducting the cyanogenation in the presence of water. The latter method is advantageous in that the introduction of the cyano group and the hydrolysis of the cyano group can be performed coincidentally by a single step and that the introduction of the cyano group can be easily achieved.

For better illustration of the compounds of the above general formula (VIII), specific examples thereof will be cited below.

(1) Naphth[2,1-d]isoxazolyl-3-alkanoic acids of the formula (VIIIa) and their salts such as:

4,5 -dihydronaphth [2, l-d] isoxazolyl-3-ethanoic acid, 7-methoxy-4,S-dihydronaphth[2,l-d]isoxazolyl- 3-ethanoic acid, 8-methoxy-4,S-dihydronaphth[2,1-d]isoxazolyl- 3-ethanoic acid, 7,8-dimethoxy-4,S-dihydronaphth[2,1-d]isoxazolyl- 3-ethanoic acid, naphth[2,l-d]isoxazolyl-3-ethanoic acid, 6-chloro-7-methoxy-naphtho[2,l-d]isoxazolyl- 3-ethanoic acid, and sodium salts, potassium salts, magnesium salts, calcium salts, aluminum salts, ammonium salts, morpholine salts, pyrine salts and choline salts of the above mentioned free acids.

(2) Naphth[2,1-d]isoXazolyl-3-alkanoic acid esters of the general formula (VIIIc) such as: 3-methoxycarbonylmethyl-4,5-dihydronaphth[2,1-d]

isoxazole,

B-ethoxyc arbonylmethyl-4,5-dihydronaphth [2, l-d] isoxazole,

3-tert-butoxycarbonylmethyl-4,5-dihydronaphth [2,1-d1isoxazole,

3-ethoxycarbonylmethyl-4,S-dihydronaphth[2,1-d]

isoxazole,

3-methoxycarbonylmethyl-4,S-dihydronaphth [2,1-d]

isoxazole,

3-methoxycarb onylmethyl-naphth [2,1-d]isoxazole,

3-methoxycarbonylmethyl- 6-chloro-7-methoxynaphth [2,1-d]isoxazole,

3-N ,N-diethylaminopropyloxycarbonylmethyl-4,5-

dihydronaphth[2,1-d]isoxazole, and

3-N,N-diethylaminoethyloxycarbonylmethylnaphth [2,1-d]isoxazole.

(3) S-carbamoylmethyl-naphth[2,1-d]isoxazoles of the formula (VIIId) such as:

This invention will now be illustrated by referring to examples.

EXAMPLE 1 FT COOCHs CHaO J O'-N I ll Y CH2OH CH3) Q 0.93 g. of lithium aluminum hydride was suspended in 100 ml. of tetrahydrofuran. Separately, 6.4 g. of 7- methoxy 3 methoxycarbonylnaphtha[2,1-d]isoxazole were dissolved in 100 ml. of tetrahydrofuran. The solution of 7-methoxy-3-methoxycarbonylnaphth[2,1-d]isoxazole dissolved in tetrahydrofuran was added into the suspension of lithium aluminum hydride in tetrahydrofuran dropwise. Then, the mixture was heated under reflux for 3 hours. After completion of the reaction, the solution was cooled to room temperature and the excessive lithium aluminum hydride was decomposed. Then the resulting inorganic substances were removed. After distilling off the tetrahydrofuran, the residue was recrystallized from methanol. Thus, 5.2 g. of 3-hydroxymethyl-7-methoxynaphth[2,1-d]isoxazole having a melting point of 151-153 C. were obtained as white platelets crystals.

[IR 1153;; 3410 cm."].

EXAMPLE 2 lil OHS) 0000211.

CHB OfCHZOH 5.6 g. of 3 ethoxycarbonyl 8-methoxy-4,5-dihydronaphth[2,1-d]isoxazole and 0.8 g. of lithium aluminum hydride were added to 100 ml. of tetrahydrofuran, followed by heating on a bath for about 2 hours. After cooling, the reaction mixture was treated with ethyl acetate and hydrochloric acid, and extracted with ether. The ether layer was treated by a customary method and then the solvent was distilled oil. The recrystallization of the residue from acetone gave 3.7 g. of 3-hydroxymethyl-8- methoxy 4,5 dihydronaphth[2,1-d1isoxazole having a melting point of 81-83 C.

EXAMPLE 3 23 g. of 3-methoxycarbonyl-4,S-dihydronaphth[2,l-d] isoxazole were dissolved into 100 ml. of tetrahydrofuran, and ml. of 70% solution of sodium dihydro-bis (2-rnethoxy) aluminate dissolved in benzene were added to the above solution with stirring. Then, the mixture was stirred for about 1 hour. Then, water was added to the mixture, and the system was treated with 10% hydrochloric acid, followed by extraction with ether. The ether solution was washed with water and after drying with salt cake, the ether was distilled ofi, and the residue was recrystal- 12 lized from acetone. Thus, 15.4 g. of 3-hydroxymethyl- 4,5-dihydronaphth[2,1-d]isoxazole having a melting point of 91-93 C. were obtained as colorless needle-like crystals.

EXAMPLE 4 3.0 g. of 6-chloro-7-methoxy 3 methoxycarbonylnaphth[2,1-d]isoxazole was dissolved in 150 ml. of anhydrous tetrahydrofuran, and 0.22 g. of lithium aluminum hydride were added to the solution with stirring, and the mixture was heated for 4 hours. After cooling the reaction mixture to room temperature, it was treated with 10% sulfuric acid solution. Then, the reacted solution was extracted with 150 ml. of chloroform, and after drying over salt cake and distilling otf the solvent, white crystals were obtained. The recrystallization of the crystals from tetrahydrofuran-ethanol gave 2.0 g. of 6-chloro-3-hydroxymethyl-7-methoxynaphth[2,l-d]isoxazole having a melting point of 210211 C. as colorless scale-like crystals.

The results of the examination of the infrared absorption spectrum and of the elementary analysis of the so obtained compound are as follows:

Infrared absorption spectrum:

1153' 3380 emf.

Elementary analysis values: Calculated (percent): C, 59.20; H, 3.80; N, 5.31. Measured (percent): C, 59.01; H, 3.72; N, 5.11.

EXAMPLE 5 OU J-COOCHs I I -CH2OH CHaOO 5.61 g. of 3-methoxycarbonyl-7-methoxy-4,S-dihydronaphth[2,1-d]isoxazole were dissolved in ml. of tetrahydrofuran, to which 0.76 g. of lithium aluminum hydride was added. This solution was heated on a Water bath for 2 hours. After cooling, a small amount of ethyl acetate was added to the reaction mixture to decompose the unreacted lithium aluminum hydride, and then ether was added for extraction after making the system acidic with hydrochloric acid. The ether layer was dried with salt cake and the solvent was distilled 01f. The recrystallization of the residue from methanol gave 4.1 g. of 3-hy droxymethyl 7 methoxy 4,5 dihydronaphth[2,1-d] isoxazole having a melting point of 108-111 C. as colorless, platelet-like crystals.

13- EXAMPLE 6 I ON I CHaOH CHQO ON l

CHQBI CHaO CHzBr CHQO \J 4.6 g. of 3-hydroxymethyl 7 methoxy-4,5-dihydronaphth[2,1-d]isoxazole were dissolved in 50 ml. of chloroform, and 8.1 g. of phosphorus tribromide were added to the solution dropwise. Then, the solution was heated on a water bath for 1 hour and was concentrated under reduced pressure. The resulting residue was recrystallized from benzene and petroleum ether. Thus, 3.2 g. of 3-bromomethyl-7-methoxy 4,5-dihydronaphth [2,1-d] isoxazole having a melting point of 9193 C. were obtained.

EXAMPLE 7 .0. CHSOOJ onion l I II 4.6 g. .of 3-hydroxymethyl 8 methoxy-4,5-dihydronaphth[2,l-d]isoxazole and 9 g. of phosphorus tribromide were added into dried chloroform, and the mixture was treated by the same procedures as adopted in Example 2 for preparing the starting compound. Thus, 4.5 g. of 3-bromomethyl 8-methoxy 4,5 dihydronaphth[2,1-d] isoxazole having a melting point of 94-96 C. were obtained.

EXAMPLE 8 0 WQ .(l

4.2 g. of the so obtained 3 hydroxymethyl-7-methoxynaphth[2,1-d]isoxazole were dissolved in 50 ml. of chloroform, and to the solution 8g. of phosphorus tribromide were added dropwise. Then, the mixture was heated on a water bathfor 1 hour, and was concentrated under reduced pressure. The remaining residue was recrystallized from benzene. Thus, 3.8 g. of 3-bromomethyl-7-methoxynaphth[2,1-d]isoxazole having a melting point of 208- 210 C. were obtained.

14 EXAMPLE 9 i? W cntorr AJHZBI 011.0 I onto I 4.7 g. of 6-chloro-3-hydroxymethyl-7-methoxynaphth [2, 1-d]isoxazole were dissolved in 50 ml. of chloroform, and 8 g. of phosphorus tribromide were added dropwise to the solution. Then, the solution was heated on a water bath for 1 hour, and was concentrated under reduced pressure. When the resulting residue was recrystallized from benzene, 4.5 g. of 6-c'hloro-3-bromomethyl-7-methoxynaphth [2,1-d]isoxazole having a melting point of 203-205 C. were obtained as colorless, needle-like crystals. The ultraviolet absorption spectrum of the compound was as follows:

A222? 253 my. (6: 22,000); 298 my (6: 6,600); 329 my (6: 3,900); 344 my (6: 4,100).

EXAMPLE 10 16.08 g. of 3-hydroxymethyl-4,S-dihydronaphth[2,1-d] isoxazole and 24.4 g. of phosphorus tribromide were treated in ml. of chloroform, by the same procedures as described in Example 6 for preparing the starting compound. Thus, 11.5 g. of 3-bromomethyl-4,S-dihydronaphth [2,1-d]isoxazole having a melting point of 87-90" C. were obtained.

EXAMPLE 11 2.6 g. of 3-bromomethyl-4,S-dihydronaphth[2.1 d] isoxazole were dissolved into 50 ml. of carbon tetrachloride, and to this solution, 12 g. of phosphorus pentachloride were added, and the solution was refluxed on a water bath for 16 hours. The reaction mixture was thrown into water, and the precipitates formed as crystals were collected by filtration, dried and recrystallized from tetrahydrofuran. Thus, 1.8 g. of 3-bromomethyl-naphth[2,l-d] isoxazole having a melting point of -187 C. were obtained as white needle-like crystals.

The results of the examination of infrared and ultraviolet absorption spectra of the above compound are as follows:

Infrared absorption spectrum:

90:0 (JUL-'1.

Ultra-violet absorption spectrum:

$13,? 258 my. (6: 21,500 343 m (e: 5,300

EXAMPLE 12 CHzBr CHIBr CHaO CHaO 2.94 g. of 3-bromomethyl-7-methoxy-4,5-dihydronaphth [2,1-d]isoxazole were dissolved in 50 ml. of chloroform, and 4.5 g. of phosphorus pentachloride were added to the solution, followed by heating under reflux for 3 hours at the temperature corresponding to the boiling point of chloroform. After completion of the reaction, the reaction mixture was thrown into ice and the chloroform layer was recovered by separation. After washing with water and drying, chloroform was distilled off, and the residue was recrystallized from chloroform and methanol. Thus, 1.6 g. of 6-chloro-3-bromomethyl-7-methoxynaphth[2,1-d] isoxazole having a melting point of 203-206" C. was obtained as colorless needle-like crystals. The ultra-violet absorption spectrum of the so Obtained compound is as follows:

A EtOH m, 253 m (6: 22,000 298 m, (6: 6,600); 329 m, (6: 3,900); 344 mu (6: 4,100).

EXAMPLE 13 Infrared absorption spectrum:

KBr

LCEN 2175 cmr EXAMPLE l4 13.2 g. of 3 bromomethyl 7 methoxy 4,5 dihydronaphth[2,l-d1isoxazole and 4.9 g. of sodium cyanide were heated under reflux for 4 hours in 100 ml. of ethanol. After completion of the reaction, the reaction mixture was thrown into about 500 ml. of water, and the formed crystals were recrystallized from methanol. Thus, 8.9 g. of 3 cyanomethyl-7-methoxy-4,S-dihydronaphth[2,l-d] isoxazole having a melting point of 1l8-121 C. were obtained as white needle-like crystals. The results of the examination of the infrared absorption spectrum and of the elementary analysis of the so formed compounds are as follows:

Infrared absorption spectrum:

IR 952%,, 2275 cm."

1 6 EXAMPLE 15 ON r I I CHaBr l HzCN CHaO LCHaO J HgCONHI CHaO ON I I H: C O O H CHsO 6.08 g. of 3 bromomethyl 7 methoxy 4,5 dihydro naphth[2,l-d1isoxazole and 2.94 g. of sodium cyanide were added to ml. of a mixed solution of equal volumes of ethanol and water, and the mixture was heated on a water bath for 7 hours. After cooling, the reaction mixture was thrown into 500 ml. of water, and the precipitate-d crude crystal. was collected by filtration and recrystallized from benzene. Thus, 4.08 g. of 3-carbamoylmethyl-7-methoxy 4,5 dihydronaphth[2,l-d]isoxazole melting at -187 C. were obtained.

flhe infrared absorption spectrum of the so obtained compound was as follows:

3250 emf, 3420 cmf 1:53 1675 emf. 2.6 g. of the so obtained 3-carba-moylmethyl-7-methoxy- 4,5-dihydronaphth[2,1-d]isoxazole were added to a solution which was made by dissolving 4 g. of sodium hydroxide in a mixed liquor of 30 ml. of methanol and 30 ml. of water, and the mixture was heated on a water bath for 3 hours to conduct the hydrolysis. Thereafter,

C O O CH;

CHJO

I II

onion 5.61 g. of 3-methoxycarbonyl 7 methoxy-4,5-dihydronaphth[2,1-d]isoxazole were dissolved in 100 ml. of tetrahydrofuran, to which 0.76 g. of lithium aluminum hydride was added. This solution was heated on a water bath for 2 hours. After cooling, a small amount of ethyl acetate was added to the reaction mixture to decompose the unreacted lithium aluminum hydride, and then ether was added for extraction after making the system acidic Momoomn cmo ]\J 17 with hydrochloric acid. The ether layer was dried with salt cake and the solvent was distilled off. The recrystallization of the residue from methanol gave 4.1 g. of 3- hydroxymethyl-7-methoxy 4,5 dihydrinaphth[2,l-d] isoxazole having a melting point of 108111 C. as colorless, platelet-like crystals.

T'll

CHzOH CHaO I ll CHzB r CHsO J T @J CHaO / I CHzCONH2 6.1 g. of 3-bromomethyl-8-methoXy-4,5-dihydronaphth- [2,1-d]isoxazole and 3 g of potassium cyanide were added to 100 ml. of a mixed solution equal volumes of methanol and water, and the mixture was heated on a water bath for 7 hours. After cooling, the reaction mixture was thrown into a great quantity of water, and the precipitates formed as crude crystals were collected by filtration. Thus, 3.9 g. of 3-carbamoylmethyl-8-methoxy- 4,5-dihydronaphth[2,1-'d]soxazole having a melting point of 194-196" C. were obtained.

$01126 O O H CHsO 2.58 g. of the so obtained 3-carbamoylmethyl-8-methoxy-4,5-dihydronaphth[2,l-d]isoxazole were added to a solution which was prepared by mixing ml. of ethanol with a solution of 3.42 g. of potassium hydroxide in 40 ml. of water, and the resulting solution was subjected to hydrolysis for 2 hours by heating on a water bath. Then, the reaction solution was thrown into 300 ml. of water and was filtered. The filtrate was made acidic with hydrochloric acid, and the precipitates formed as crude crystals were 18 collected by filtration and recrystallized from methanol. Thus, 2.1 g. of 3-hydroxycarbonylmethyl-8-methoxy-4,5- dihydronaphth[2,1-d]isoxazole having a melting pointiof l86188 C. were obtained. i

(Infrared absorption spectrum:

v58 1720 emf).

EXAMPLE 17 5.28 g. of 3 bromomethyl-4,5-dihydronaphth[2,l-d] isoxazole and 3 g. of sodium cyanide were added into ml. of hydrous alcohol, and the solution was heated on a water bath for 5 hours. After completion of the reaction, the reaction mixture was through into water, and the precipitates formed as crude crystals were collected by filtration and recrystallized from benzene. Thus, 3.75 g. of 3-carbamoylmethyl 4,5 dihydronaphth[2,1-d]isoxazole having a melting point of -1675" C. were obtained.

The infrared absorption spectrum of the so obtained compound was as follows:

11%? 3240 emf, 3430 cmr v53 1670 emr cmooNm cmcoon 2.3 g. of so obtained 3-carbamoylmethyl-4,5-di-hydronaphth[2,1d]isoxazole were added into a mixed solution of 40 ml. of 10% aqueous solution of potassium hydroxide and 20 ml. of ethanol, followed by heating on a water bath for 2 hours. After completion of the reaction, the reaction mixture was thrown into water and made acidic with hydrochloric acid. The precipitates formed as crude crystals were recrystallized from acetone. Thus, 2.01 g. of 3-hydroxycarbonylmethyl-4,S-dihydronaphth[2, l-d] isoxazole having a melting point of -1 83 C. were obtained.

(Infrared absorption spectrum:

#33 1725 CHI- EXAMPLE 18 T1 O-T' CHzBl' I CHQCN L J-) H T CHzCOOH @yomoomn 5.2 g. of 3-bromomethyl-naphth[2,l-d]isoxazole and 2.0 g. of sodium cyanide were heated under reflux for 5 hours in a mixed solution of 50 ml. of ethanol and 20 ml. of water. After completion of the reaction, the reaction mixture"was throwninto 300 ml. of water, and the precipitates formed as crystals were collected by filtration. Thus 4.1 g. of 3-carbamoylmethylnaphth[2,1-d]isoxazole were obtained as crystals. This compound was heated for 1 hour together with 1.6 g. of sodium hydroxide, 30 ml. of methanol and 50 ml. of water for hydrolysis. After completion of the reaction, the reaction mixture was made acidic with hydrochloric acid and the precipitates were formed as white crystals. The recrystallization of the so obtained white crystals from methanol gave 3.2 g. of naphth[ 2,l-d] isoxazolyl-ethanoic acid having a melting point of 182- 185 C.

[IR V52, 1725 cm.

The starting compound was obtained by treating 3- bromomethyl 4,5 dihydronaphth[2,1-d]isoxazole with chloranil or phosphorus pentachloride in carbon tetrachloride.

EXAMPLE l9 ON II I CHzBr ON i ll I CHzCN c1130 CH2COOH CHaO I 6.5 g. of 3 bromomethyl-6-chloro-7-methoxynaphth [2,1-d]isoxazole and 2.0 g. of sodium cyanide were heated under reflux for hours in a mixed solution of 50 ml. of ethanol and ml. of water. After completion of the reaction, the reaction mixture was thrown into 300 ml. of water, and the precipitates formed as crystals were collected by filtration. Thus 4.8 g. of 3-carbamoy1methyl-6- chloro-7-methoxynaphth[2,1-d1isoxazole were obtained. The crystals were heated for 1 hour together with 1.6 g. of sodium hydroxide, ml. of methanol and 50 ml. of water for performing the hydrolysis reaction. After completion of the reaction, the reaction mixture was made acidic with hydrochloric acid to precipitate White crystals. The so formed crystal precipitates were recrystallized from methanol. Thus, 3.0 g. of 6-chl0r0-7-methoxynaphth[2,l-d] isoxazolyl-ethanoic acid having a melting point of 179- l81 C. were obtained as white platelet-like crystals.

[IR 1 5?; cm. 1718 (C=O).]

CHzCOOH CH: O i

EXAMPLE 21 5.8 g. of 3-cyanomethyl-4,S-dihydronaphth[2,l-d] isoxazole were added to ml. of a mixed solution of equal volumes of ethanol and 10% aqueous solution of sodium hydroxide, and the solution was heated on a bath for 3 hours. After completion of the reaction, the reaction mixture was thrown into 500 ml. of water and made acidic with hydrochloric acid. Then, the so obtained 4.4 g. of 4,5 dihydronaphth[2,l-d]isoxazolyl-3-ethanoic acid was recrystallized from acetone to form sand-like crystals having a melting point of 181183 C.

EXAMPLE 22 I j ooooul Q3 r CHsO I 000cm smog 2.6 g. of 7-methoxy-3-methoxycarbonyl-4,S-dihydronaphth[2,1-d]isoxazole were dissolved in 50 ml. of carbon tetrachloride, and to the solution 12 g. of phosphorus pentachloride were added. After heating under reflux on a water bath for 16 hours, the reaction mixture was poured intoice water. The formed crystal precipitates were collected by filtration, dried and recrystallized from tetrahydrofuran. Thus, 1.8 g. of 7-methoxy-3-methoxycarbonylnaphth[2,1-d]isoxaz0le was obtained as white needle-like crystals.

The results of examination of infrared and ultra-violet absorption spectra and of the elemental analysis of the so obtained compound are as follows:

Infrared absorption spectrum:

21 Ultra-violet absorption spectrum:

x359 259 m (6: 21,000 343 mu ((-1: 5,300

Elemental analysis values: Calculated (percent): C, 65.37; H, 4.28; N, 5.45. Measured (percent): C, 65.59; H, 4.21; N, 5.39.

EXAMPLE 23 ON CH I I CHzOH CHaO CHsO QCH CI CHaO CH COOH I l CHZON CHaO CHQO C1 Cl .0 g. of 8-methoxy-3-methoxycarbonylnaphth[2,1-d] isoxazole were dissolved in 50 ml. of anhydrous tetrahy drofuran, and 0.19 g. of lithium aluminum hydride powder was added to the solution with stirring. Then, the mixture was heated under reflux for 3 hours. After cooling the solution to room temperature, it was treated with 10% sulfuric acid solution. Then, 50 ml. of benzene were added to the reaction mixture for extraction, and after drying over anhydrous sodium sulfate, the solvent was distilled off. The formed crystals were recrystallized from methanol. Thus, 1.5 g. of 3-hydroxymethyl-8-methoxynaphth[2,1-d]is0xazole having a melting point of 153- 155 C. were observed as white prism-like crystals. The compound exhibited an absorption at in the infrared absorption spectrum. The elementary analysis values of the so obtained compound are as follows: Calculated (percent): C, 68.11; H, 4.84; N, 6.11. Measured (percent): C, 67.92; H, 4.80; N, 5.95. 4.2 g. of 3-hydroxymethyl-8-methoxynaphth[2,1-d] isoxazole obtained in accordance with the above method were dissolved in 50 ml. of chloroform, and 17 g. of phosphorus pentachloride were added to the solution. The solution was heated under reflux on a water bath for 16 hours. Then, the reaction mixture was poured into ice water, and the formed crystals were collected by filtration, dried and recrystallized from tetrahydrofuran. Thus, 4.0 g. of 7-chloro-3-chloromethyl-8-methoxynaphth[2,1- d]isoxazole having a melting point of 214-217 C. were obtained. The ultra-violet absorption spectrum of the compound was as follows:

EtOH ML 251 mu (e=2l,500); 298 mu (e=6,500); 328 m (e=4,000); 345 my (e=4,100).

The so obtained 7-chlor0-3-chloromethyl-8-methoxynaphth[2,l-d]isoxazole was treated in the same manner as described in Examples -20. Thus, 2.5 g. of 7-chloro- 8-methoxynaphth[2,1-d]isoxazolyl-3-ethanoic acid having a melting point of 201-204 C. were obtained, and it exhibited an absorption at in the infrared absorption spectrum.

EXAMPLE 24 C330 omen omo omooon x3323? 251 mp. (e=21,500); 298 mu (e=6,500); s28 m, (e=4,000); 345 my (e -4,100).

8.02 g. of 7-chloro-3-chloromethyl-8-methoxynaphth [2,1-d]isoxazole prepared in accordance with the above method were disolved in a mixed solution of equal volumes of water and ethanol together with 5 g. of sodium cyanide, and the mixture was treated in the same manner as described in Examples 15-20. Thus, 4.5 g. of 7-chloro- S-methoxynaphth [2, l-d] isoxazolyl-3-ethanoic acid having a melting of 203 C. were obtained.

EXAMPLE 25 CH3 0 P01 Mot er I /VCHzCOOH CHaOQV All 2 g. of 3 hydroxymethyl-7-methoxy-4,S-dihydronaphth [2,1d]isoxazole were dissolved in 50 ml. of carbon tetrachloride, and g. of phosphorus pentachloride were further added thereto. Then, the solution was heated under reflux for 16 hours on a water bath. The reaction mixture was poured into ice water, and the formed crystals were collected by filtration, dried and recrystallized from tetrahydrofuran. Thus, 1.9 g. of 6-chloro-3-chloromethyl- 7-methoxynaphth[2,1-d]isoxazole were obtained.

1.9 g. of 6-chloro-3-chloromethyl-7-methoxynaphth [2,1]isoxazole prepared in accordance with the above method were dissolved in a mixed solution of equal volumes of water and methanol together with 1.5 g. of sodium cyanide, and the mixture was treated in the same manner as described in Examples 15-20. Thus, 1.1- g. of

v3-hydroxycarbonylmethyl-6-ch'loro 7 methoxynaphth [2,1-d]isoxazole melting at 179-18l C. were obtained, and it exhibited an absorption at v 1718 cm.

in the infrared absorption spectrum.

. ohloranil 0-'N CHZCN CHaO /\CH2COOH cino- 24 over salt cake. Then, the solvent was distilled oil and the residue was recrystallized from. methanol. Thus, 2.75 g. of 3-chloromethyl 7 methoxynaphth[2,l-d]isoxazole having a melting point of l32-l34 C., were obtained as white needle-like crystals and its exhibited the following absorptions in the ultraviolet absorption spectrum UV A523? 228 m (e=17,000); 250 m... (e=22,000); 288

m (e=14,000); 336 m (e=2,000).

The elementary analysis values of the above compound are as follows:

Calculated (percent): C, 53.04; H, 4.07; N,5.66. Measured (percent): C, 62.98; H, 4.21; N, 5.69.

2.5 g. of 3-chloromethyl-7-methoxynaphth[2,l-d]isoxazole obtained by the above method and 1.7 g. of sodium cyanide were dissolved in a mixed solution of water and ethanol, and the solution was treated in the same manner as described in Examples 15-20. Thus, 1.2 g. of 7-methoxy naphth[1,2-d]isoxazolyl-3-ethanoic acid having a melting point of 18919l C. were obtained and it exhibited an absorption at E25 1720 cm.-

in the infrared absorption spectrum.

2.5 g. of 3-chloromethyl-7-methoxy-4,5-dihydronaphth [2,1-d]isoxazole were dissolved in 50 m1. of chloroform, and 4.5 g. of phosphorus pentachloride were added thereto. Then, the solution was heated under reflux for 3 hours at the temperature corresponding to the boiling point of chloroform. After completion of the reaction, the reacted mixture was poured into ice water, and the chloro form layer was separated, and the chloroform was distilled 01f according to a customary method. The resulting crude crystals were recrystallized from a mixed solvent of chloroform and methanol. Thus, 1.8 g. of 6-chloro-3- chloromethyl 7 methoxynaphth[2,1-d]isoxazole melting at 212214 C. were observed as colorless needle-like crystals and exhibited the following absorptions in the ultra-violet absorption spectrum:

AELOH 230 mp (=25,000); 252 m (e=39,000); 292 m (=16,500) 344 mp (5:2,900).

4.5 g. of 6-ch1oro-3-chloromethyl-7-methoxynaphth[2,1- d]isoxazole obtained by the above method and 2.0 g. of potassium cyanide were dissolved in a mixed solution of equal volumes of water and ethanol, and the mixture was treated in the same manner as described in Examples 15- 20. Thus, 3.1 g. of 6-chloro-3-hydroxycarbonylmethyl-7- EXAMPLE 28 om... (1) a 4 g. of 3-methoxycarbonylnaphth[2,1-d]isoxazole were CHzCN dissolved in 50 ml. of anhydrous tetrahydrofuran, and the solution was treated in the same manner as described in the method for preparingthe starting compound of Example 1. Thus, 3 g. of 3-hydroxymethylnaphth[2, 1-d] isoxazole having a melting point of 145-146 C. were obtained.

5 g. of 3-hydroxymethylnaphth[2,1-d]isoxazole obtained by the above method was dissolved in 50 ml. of chloroform, and the solution was subjected to bromination in the same manner as described in Example 6. Thus, 4.7 g. of 3-bromomethylnaphth[2,1-d1isoxazole melting at 187-l88 C. were obtained.

4 g. of the so obtained 3-bromomethylnaphth[2,1-d] isoxazole were treated in the same manner as described in Examples 16 and 17. Thus, 3 g. of naphth[2,1-d] isoxazolyl-3-ethanoic acid having a melting point of 182-185 C. were obtained and exhibited an absorption at KBr C=O 1725 emsin the infrared absorption spectrum.

EXAMPLE 29 FT @Acmcoon PO C2H5 CHiO HO(CH2)3N\ CzHs 5.2 g. of 7 methoxy 4,5 dihydronaphth[2,l-d]isoxazolyl 3 ethanoic acid were dissolved in 100 ml. of chloroform, and 4.16 g. of phosphorus pentachloride were gradually added to the solution at room temperature with stirring. Chloroform or phosphoryl chloride was distilled olf under reduced pressure. A solution of 4.1 g. of N,N- dimethylaminoisopropanol in 50 ml. of benzene was added dropwise to the solution over aperiod of about 20 minutes. Thereafter, the stirring was conducted at room temperature for 2. hours and the solution was heated at 50-60 C. for 30 minutes. Then, the solution was cooled to room temperature and was washed twice with 50 ml. of water. The organic layer was dried with salt cake and then benzene was distilled 05. Thus, .an oily substance was obtained. The oily substance was dissolved in ether, and hydrochloric acid gas was blown into the solution to precipitate white crystals. The formed crystals were collected and wererecrystallized from ethyl acetate-methanol, Thus, 4.5 g. of N,N-dimethylamino'- isopropanol ester hydrochloride of 7 -methoxy- 4,5-dihydronaphth[2,l d]isoxazolyl-3 ethanoic ;acid melting at 178-180 C. were obtained as white crystals. The results of the examination of p the infrared and ultra-violet absorption spectra and of the elementary analysis of the so obtained compound are as follows:

Infrared absorption spectrum:

IR use, 1746 cutand IR 3" I I I Q CILCOOIT I ll CH 3 CH2CONHCH2CH2N CHa HzN C 112C H2N 5.7 g. of 4,5-dihydronaphth[2,1-d]isoxazolyl-3-ethanoic acid were dissolved in ml. of chloroform, and 6.24 g. of phosphorus pentachloride was added gradually thereto. Then, the solution was heated at 40-50 C. for 2 hours. After completion of the reaction, chloroform and phosphoryl chloride were distilled off, and the residue was dissolved in 200 ml. of dried benzene, and the solution was stirred at room temperature. 4.4 g. of N,N-dimethylaminoethylamine dissolved in 50 ml. of benzene were gradually added dropwise to the above solution. Then, the solution was stirred at room temperature for 3 hours, and was heated at 50-60 C. for 30 minutes. After the reaction mixture had been cooled to room temperature, it was washed twice with 50 ml. of water, and the organic layer was dried over salt cake. Then, benzene was distilled off. The residue was dissolved in ether, and hydrochloric acid gas was blown into the ether solution to precipitate white crystals. Then, the crystals were collected by filtration and recrystallized from a mixed solution of ethyl acetate and methanol. Thus, 3.2 g. of hydrochloride of 3 N,N-dimethylaminoethylcarbamoyhnethyl 4,5-dihydronaphth[2,1-d]isoxazole having a melting point of 245- 248" C. were obtained as white needle-like crystals and exhibited absorptions at #333; 2660 0m? ($111 and 1640 cm? (0-0 'ofupito 4 carbon atoms, and Halogen, ring" V p 2-7 'What weclaimrist' 1 r 1 1. A'compound of the;formula*z wherein ring Ahas O- -Z 'sHbst'ituents selectedfrom' the group consisting-of alkoxy or up to 4 carbon atoms, alkyl i p 'may-ha've a fcarb'on-to-carbQn doublelbond between the positiohs" of C-4 and C-5 ,'arid R represents a hydroxyl "group, a'halogen atomor a cyano group. I y g V Q A om unded wherein ring Alias 0-2 substituents'selected from the group o sist n of .a k xy W104 c rb atoms, alkyl of up to 4 carbon atoms, 'an d halogemiand ring ]3 may have acarbon-to-carbo'n double bond=between the positionsofC-4andC-5.,,

3. The compound o f claim" 2,-wherein said compound is 3-hydroxymethyl-4,S-dihydronaphth [2,1-d] isoxazol.

4. The compound of claim 2, wherein said compound is 3-hydroxymethyl-naphth 2, 1-d]isoxazol.

5. A compound of the formula CHzCN A I B wherein ring A has 02 substituents selected from the group consisting of alkoxy of up to 4 carbon atoms, alkyl of up to 4 carbon atoms, and halogen, ring B may have a carbon-to-carbon double bond between the positions of C-4 and C-5, and X is a halogen.

9. The compound of claim 8, wherein said compound is 3-chloromethyl-4,S-dihydronaphth[2,1-d]isoxazol. '10. The'com'po'und of claim 8, wherein said compound 'is- Q brQmQrnethyl-naphth[2,1-d1is0xazol. i

p n I References Cited 1 A v Morrison et all: OrganicChemistry, Allyn and Bacon (1959), 365-443, 445, 810. 1 RA MONDV. RUSH, Primary Examiner U.S.' c1. X.R.

260 -2475 inf-26 s 17c, 293.58; 424246, 250, 267, 27;

. UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,842,099 Dated October 15. 1974 Invent0r(s) v Yasushi SUZUKI ET AL It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In the Heading, insert patentees' Foreign Application Priority Data as follows:

-- Japanese Application 43-72990/68, filed October 8, 1968; Japanese Application 43-72991/68, filed October 8, 1968; Japanese Application 44-32241/69, filed April 26, 1969; Japanese Application 44-32242/69, filed April 26, 1969; and Japanese Application 44-32243/69, filed April 26, 1969.

Correct the spelling of the assignee to read as follows:

-- Teikoku Hormone Mfg. Co. Ltd.

Signed and sealed this 14th day of January 1975.

(SEAL) Attest:

McCOY M'. GIBSON JR. (2; MARSHALL DANN Attesting Officer Commissioner of Patents FORM po'wso USCOMM-DC common I k V [1.5: GOVERNMENT PRINTING OFFICE l9) 0-365-33L 

1. A COMPOUND OF THE FORMULA 